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Tay-Sachs disease, the prototype of the lysosomal sphingolipid storage disorders, is a hereditary disorder involving the accumulation of a ganglioside, GM2.  The enzymatic defect in Tay-Sachs disease is a deficiency of the lysosomal enzyme beta-hexosaminidase A (HEX A or GM2 gangliosidase)155, which is responsible for the cleavage of a terminal N-acetylgalactosamine from the GM2 ganglioside. Diagnosis

Diagnosis is on clinical grounds with confirmation by biochemical analysis of beta-hexosaminidase A in serum, leucocytes and skin. Inheritance

All of the variant forms of GM2 gangliosidosis are inherited as an AR trait. Myoclonus

Watson and Denny-Brown described three families with familial amaurotic familial idiocy, in which myoclonus was present with movement or sudden stimuli156.  In addition, seizures were precipitated by passive movement, sound and light in one case.  In the third case a sudden passive movement would result in violent, clonic contractions of the muscle at first confined to the joint moved, but spreading rapidly if passive stretch was repeated.  Sudden loud sounds or light flashes led to symmetrical clonic flexion movements of both upper and lower limbs and if this was repeated at a particular rate, the clonic response became self-sustained and resulted in a generalized seizures. Clinical manifestations

Infantile onset

The infantile onset form is characterized by an excessive startle response.  As the disease progresses, motor development slows and the children are unable to learn to sit, with associated axial hypotonia, increased tone, hyperreflexia and macular cherry-red spots157.  During the second year of life, macrocephaly becomes apparent, presumably caused by intraneuronal storage of gangliosides and other lipids, and concomitantly, seizures may develop which can be induced by auditory stimuli.  Myoclonus is characteristic of the initial stages 23.  Between the second and third years of age the children become severely cognitively impaired, decerebrate, blind, and unable to respond to most stimuli.




The late-onset (juvenile/adult) variant of GM2 gangliosidosis, and has an indolent clinical presentation.  Although this variant has been called the "adult-onset variant," the illness usually begins in adolescence.  Early gross motor development is normal, although affecteds are are often considered clumsy and awkward as children.  An intention tremor, frequently seen in the first decade, may be the first indication of a neurologic problem.  Dysarthria also develops early, and difficulties in school may also be apparent.  Myoclonus or seizures may be prominent early symptoms 23;69.  Dementia, ataxia, spasticity and dystonia present later69;157.  During adolescence, proximal muscle weakness begins with fasciculations and atrophy that has an appearance of juvenile-onset spinal muscular atrophy158.  Development of a broad-based ataxic gait usually follows, making walking even more difficult.  Patients have may present in adulthood with depression, visual hallucinations, paranoid delusions and catatonic states159 160. Special Investigations

Enzyme analysis remains the most effective means of diagnosing patients with GM2 gangliosidosis.  Although neuroradiological studies may be normal at first, the CT head scans in children with GM2 gangliosidosis eventually show low density in the basal ganglia and white matter, and increased signal intensity on T2-weighted MRI 161.  Late-onset forms of GM2 gangliosidosis have prominent cerebellar atrophy, especially of the vermis, but a normal-appearing cerebral cortex on CT or MRI scans, despite cognitive decline and psychosis159.

Initially, the EEG in Tay-Sachs disease will frequently show slowing, but when seizures develop multifocal spikes may appear.  Watson and Denny-Brown’s case showed generalized synchronous and asynchronous bilateral spike and slow wave activity on a generally slow background with periodic bursts of slow waves156.

Electron microscopic analysis of skin, conjunctiva, and rectal mucosa biopsies frequently shows storage of membranous cytoplasmic bodies or other electron-dense storage material within nerve cells and myelinated and unmyelinated axons162.  Neuropathological findings characteristically are ballooning of neurons, with massive intralysosomal accumulations of lipophilic membranous bodies. Neuropathology

A child with seizures and myoclonus came to autopsy, where all neurons were seen to be distended with lipid granules; there was extensive degeneration of cerebral cortex, and involvement of basal ganglia including globus pallidus, putamen and thalamus.  In the cerebellum, there was diffuse atrophy, with a virtually absent granular cell layer, marked reduction in Purkinje cells, and widespread gliosis163. Epidemiology

Tay-Sachs disease is inherited as an AR disorder.  People of Eastern or Central European Jewish ancestry have a predilection for this disease, but other populations, specifically French-Canadians, also have a higher than average incidence of the disease.  The carrier frequency is estimated to be 1 in 31 in the Jewish population and 1 in 277 in non-Jewish populations164. Management

Valproic acid appears to be the most efficacious anticonvulsant, and clonazepam and other benzodiazepines may prove effective in controlling severe irritability and psychiatric symptoms160.



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  157.   Meek D, Wolfe LS, Andermann E, Andermann F. Juvenile progressive dystonia: a new phenotype of GM2 gangliosidosis. Ann Neurol 1984;15:348-52.

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  164.   Kaback M, Lim-Steele J, Dabholkar D, Brown D, Levy N, Zeiger K. Tay-Sachs disease--carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA 1993;270:2307-15.